Process for the manufacture of quinazoline compounds



United States Patent PROCESS FOR THE MANUFACTURE 0F QUINAZOLENE COMPGUNDS Hans islet, Bottmingen, and Albrecht Hiini, Basel, Switzerland, assignors to Ciba Pharmaceutical Products,

Inc, urnmit, N. .F.

No Drawing. Application December 7, 1950, Serial No. 199,717

Ciairns priority, application Switzerland December 23, 1949 9 (Ilaims. (Ci. 260-2564) The present invention relates to a new process for the manufacture of quinazoline compounds, the carbon atom of which in 2-position is attached to the nitrogen atom of a cyclic amino compound of aromatic character and the carbon atom of which in 4-position is attached to the nitrogen atom of an amino compound of aliphatic character, which contains a further strongly basic group in addition to the amino group.

It is known that these compounds can be produced by reaction of quinazoline compounds which contain one of the said amino groups in one of the positions 2 and 4 and a halogen atom in the other of these two positions, with the corresponding amine.

A primary object of the present invention is the embodiment of a process for more advantageously preparing the said quinazoline compounds. This object is realized, according to the present invention, by heating a 2,4-diha1ogen quiuazoline simultaneously with an amino compound of aliphatic character which, in addition to the amino group, contains a further strongly basic group and with a cyclic amino compound of aromatic character. The 2,4-dihalogen quinazoline, which preferably is the 2,4-dichloro compound, may be further unsubstituted or may contain substituents. The amino compounds of aliphatic character which are employed as starting materials according to this invention include more especially amino-, such as dialkylaminoor alkylenimino-, for instance piperidino-, alkylamino compounds, the alkylene residues of which may also be interrupted by a hetero atom, such as oxygen or sulfur, for example dialkylamino-alkylthio-alkylamino or morpholino-alkylamino compounds. As cyclic amino compounds of aromatic character, use may be made of aromatic amino cornpounds or of heterocyclic amines of aromatic character, but the preferred compounds in this category are the amino thiazole compounds.

The reaction is advantageously carried out in a diluent, such as water, alcohol, dioxane or nitrobenzene. The reaction may, if desired, be carried out under superatmospheric pressure.

The following examples illustrate the invention in greater detail. The relation between parts by weight and parts by volume is the same as that between grams and cubic centimeters. Percentages are by weight; temperatures are in degrees Centigrade.

Example 1 A mixture of 175 parts by weight of 2,4-dichloroquinazoline, 3000 parts by volume of nitrobenzene, 154 parts by weight of 2-amino-4-phenyl-thiazole and 102 parts by weight of p-diethylamino-ethylamine is heated to a bath temperature of 170-175. After the reaction solution has been maintained at this bath temperature for 3 to 4 hours, it is allowed to cool and the salt which crystallizes out is separated by suction filtration. It is recrystallized from a mixture of 2000 parts by volume of 96% ethanol and 250 parts by volume of water with addition of animal charcoal, the crystallization being "ice favored by addition of 400 parts by volume of ethyl acetate. The thus-obtained dihydrochloride of the 2-[4'- phenyl thiazolyl -(2)- amino] 4 -(fl-diethylamino-ethylamino)-quinazoline which corresponds to the formula 1]Q'HCH2CH2N(OH)2 can be extracted with acetone for removal of the solvent present. It melts at 264-266" (with decomposition).

By proceeding in the manner described in the preceding paragraph, but replacing the recited reactants by equivalent quantities of the hereinafter-specified starting materials, the following compounds are obtained:

2-[6'- methyl-benzthiazolyl -(2')- aminol-4-(fi-diethylamino-ethylamino)-quinazoline which melts at 189-191", from 2,4-dichloro-quinazoline, [i-diethylamino-ethylamine and Z-amino-6-methyl-benzthiazole;

2 [benzthiazolyl- 2 -arnino -4- (fi-diethylamino-ethylamino)-quinazoline which melts at 216218, from 2,4- dichloro-quinazoline, fi-diethylamino-ethylamine and 2- amino-benzthiazole;

2 [thiazo1yl(2)- amino] 4 -([i diethylamino-ethylamino)-6-chloro-quinazoline which melts at 1805-181", from 2,4,6-trichloro-quinazoline, fl-diethylamino-ethylamine and Z-aminothiazole;

2 -[benzimidazolyl -(2)- amino]- 4 -(,6 diethylaminoethylamino)-6-chloro-quinazoline which melts at 196- 197", from 2,4,6-trichloro-quinazoline, 2-amino-benzimidazole and fi-diethylamino-ethylamine;

2 [6' methyl benzimidazolyl (2) amino] 4 (5 diethylamino ethylamino) quinazoline which melts at 225-227", from 2,4-dichloro-quinazoline, fi-diethylaminoethylamine and Z-amino-6-methyl-benzimidazole;

2 {6' methyl benzthiazolyl (2) amino] 4 (7 diethylamino propylamino) quinazoline which melts at 202204, from 2,4-dichloro-quinazoline, 2- amino-6-methyl-benzthiazole and 'y-diethylamino-propylamine;

2 [6 chloro benzthiazolyl (2) amino] 4 (/3-diethylamino-ethylamino)-quinazoline which melts at 210211, from 2,4-clichloro-quinazoline, 2-amino-6- chloro-benzthiazole and [3-diethylamino-ethylamine;

2 [6' methoxy benzthiazolyl (2') amino] 4 e-diethylamino-ethylamino -6-chloro-quinazoline which melts at 197-198", from 2,4,6-trichloro-quinazoline, 2- amino-6-methoxy-benzthiazole and fi-diethylamino-ethylamine;

2 [4,7 dimethyl benzthiazolyl (2') amino] 4-(,8-diethylamino-ethylamino)- quinazoline which melts at 205207, from 2,4-dichloro-quinazoline, 2-amino- 4,7-dimethyl-benzthiazole and fi-diethylamino-ethylamine;

2 [6,7' benzo benzthiazolyl (2) amino] 4 (,B-diethylamino-ethylamino)-quinazoline which melts at 220222, from 2,4dichloro-quinazoline, 2-amino-6,7- benzo-benzthiazole and ,8-diethylamino-ethylamine;

2 [6 nitro benzthiazolyl (2') amino] 4 (,6- diethylamino-ethylamino)-quinazoline which melts at 304306, nitro-benzthiazole and fi-diethylamino-ethylamine;

2 [4 methyl benzthiazolyl (2') amino] 4 (,B-diethylamino-ethylamino)-quinazoline which melts at 193-195, from 2,4-dichloro-quinazoline, 2-amino-4- methyl-benzthiazole and fi-diethylamino-ethylamine;

2 [6 cyano benzthiazolyl (2) amino] 4 ([3 diethylamino-ethylamino)-quinazoline which melts at 289292, from 2,4-dichloro-quinazoline, 2-amino-6- cyano-benzthiazole and B-diethylamino-ethylamine;

2 [6 n butoxy benzthiazolyl (2) amino] 4 from 2,4-dichloro-quinazoline, 2-amino-6- o In (fl-diethylamino-ethylamino)-quinazoline which melts at l68l69, from 2,4-dichloro-quinazoline, 2-amino-6-nbutoxy-benzthiazole and ,B-diethylamino-ethylamine;

2 [6 acetamino benzthiazoiyl (2) amino] 4 (fl-diethylamino-ethylarnino)-quinazoline which melts at 252257, from 2,4-dichloro-quinazoline, 2-amino-6-acetamino-bcnzthiazole and ,B-diethylamino-ethylamine;

2 [6' methyl benzthiazolyl (2') amino] 4 (fl-pipcridino-ethylamino)-quinazoline which melts at 204-206, from 2,4-dichloro-quinazoline, 2-ami'no-6- methyl-benzthiazole and fl-piperidino-ethylamine;

2 [4' (p bromo phenyl) thiazolyl (2) amino] 4- fi-diethylamino-ethylamino -quinazoline which melts at 219221, from 2,4-dichloro-quinazoline, 2-a1nino-4- (p-bromo-phenyl)-thiazle and B-diethylamino-ethylamine;

2 [4,5' diphenyl thiazolyl (2) amino] 4 5-diethylamino-ethylamino)-quinazoline which melts at 198402", from 2,4-dichloro-quinazoline, 2-amino-4,S- diphenylthiazole and B-diethylamino-ethylamine;

2 [6 methyl benzthiazolyl (2) amino] 4 l"-diethylamino-butyl- 3 -amino -quinazoline which melts at 142-143, from 2,4-dichlor0-quinazoline, 2- amino-6-methyl-benzthiazole and l-diethylamino-butyl- (3)-amine;

2 [6' methylsulfonyl benzthiazolyl (2) amino] 4-(5-diethylamino-ethylamino)-quinazoline which melts at 267269, from 2,4-dichloro-quinazoline, 2-amino-6- methyl-sulfonyl-benzthiazole and B-diethylamino-ethylamine;

2 [6' benzyl benzthiazolyl (2') amino] 4 (,B diethylamino-ethylamino)-quinazoline which melts at 216218, from 2,4-dichloro-quinazoline, 2-amino-6- benicyl-benzthiazole and fi-diethylamino-ethylamiue;

2 [4,6' dimethyl benzthiazolyl (2) amino] 4 ({3-Ciiethylamino-ethylamino)-quinazoline which melts at 210--2l3, from 2,4-dichloro-quinazoline, 2-amino-4,6- dimcthyl-benzthiazole and fl-diethylamino-ethylamine;

2 [6' sulfonamido benzthiazolyl (2') amino] 4- p -diethylamino-ethylamino) -quinazoline which melts at 257269, from 2,4-dichloro-quinazoline, 2-amino-6- sulfcnamido-benzthiazole and ,8-diethylamino-ethylamine;

2 [4 (p tolyl) thiazolyl (2) amino] 4 (,B-diethylamino-ethylamino)-quinazoline which melts at 181-l83, from 2,4-dichloro-quinazoline, 2-amino-4-(ptolyll-thiazole and ,B-diethylarnino-ethylamine;

2 [6' pheuoxy benzthiazolyl (2) amino] 4 (B-diethylarnino-ethylamino)-quinazoline which melts at 197.5-198, from 2,4-dichloro-quinazoline, 2-amino-6- pheuoXy-benzthiazole and ,B-diethylamino-ethylamine;

2 [6' methyl benzthiazolyl (2) amino] 4 [,8 (,8 diethylamino-ethylthio) ethylamino] quinazoline which melts at 191-193", from 2,4-dichloroquinazoline, 2-arnino-6-methyl-benzthiazole and B-(B-diethylamino-ethyl-thio) -ethylamine.

Example 2 uct is suction-filtered from a small quantity of insoluble 5 matter which is present and, by the addition of concentrated hydrochloric acid, the dihydrochloride of 2(pchloranilino) 4 (,8 diethylamino ethylamino) quin azcline of the formula IYIHCHzCHzN (C2H )z /\LII is caused to crystallize. After recrystallization from ethanol, it melts at 266462". From its aqueous solution by treating with caustic aikali solution, extraction with hioroform and recrystallization of the chloroform residue tom benzine, the base of melting point 1l2l 3 is obained.

Example 3 8 parts by weight of 2,4-dichloro-quinazoline are heated, with stirring to 200 together with 5 parts by weight of p-chlorauhne 4.6 parts by weight of fi-diethylaminoethylamine. After the reaction mass has cooled, it is taken up in heated dilute hydrochloric acid and then rendered alkaline with caustic soda solution. Extraction is carried out with chloroform and the extract is shaken out with 5% acetic acid. liter filtering through animal charcoal there obtained, upon addition of concentrated hydrochlor c acid to the hot acetic acid solution, the 2-(pchlorann o 4 (5 diethylamino ethylamino) quinazoiiue dihydrochloride, from which the free base which melts at ll2-ll3 may be obtained in the manner indicated in Example 2.

By proceeding in the manner described in the preceding paragraph, but replacing the recited reactants by equivalent quantities of the hereinafter-specified starting materials, the following compounds are obtained:

2 (p chlor aniline) 4 ('y diethylarnino propyl smino)-quinazoline which melts at l25-127, from 2,4- dichloro-quinazoline, p-chloraniline and 'y-diethylaminopropylamine;

2 (p toluidino) 4 (7 diethylamino propyl amino)quinazolinc which melts at 93-94", .rom 2,4-dichloroquinazoline, p-toluidine and -diethylamino-propylamine;

2 {[3 naphthylarnino) 4 ('y diethylamino pro pylarnino)-quinazoline which melts at l42, from 2,4-dichloro-quinazoiine, B-naphthylamine and 'y-diethylainino-propylamine;

2 (p anisidino} 4 ('y diethylamino propyl amino)-quinazoline which melts at ll2114, from 2,4- dichloro-cguinazoline, p-anisidine and y-diethylamino-propylarnine;

2 (5 naphthylamino) 4 ([3 diethylamino ethyl amino)-quinazoline which melts at 126l27, from 2,4- dichloro-quinazoline, fi-naphthylamine and fl-diethylamino-ethylamine.

Having thus disclosed the invention what is claimed is:

1. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline with a primary aliphatic amine of the formula wherein x stands for a member selected from the group consisting of alkyiene radicals and alkylene radicals interrupted by hetero atoms and y stands for a tertiary amino group, and simultaneously with a member selected from the group consisting of arylamincs, Z-amino-thiazoles and Z-amino-imidazoles, said hetero atoms being selected from the group consisting of oxygen and sulfur.

2. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline With a diallcylamino-alkylamino compound and simultaneously with a Z-arnino-imidazole.

3. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline with a dialkylarnino-a nylarnino compound and simultaneously with a phenylarnine.

4. A process for the preparation of a quinazoline cornpound, which comprises heating a 2,4-dichloro-quinazoline with a dialkylamino:lkylamino compound and simultaneously with a Z-arnino-thiazole.

5. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline with a dialkylaniino-alkylamino compound and simultaneously with a 2-arnino-benzthiazoie.

6. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline with fl-diethylamino-ethylamine and simultaneously with 2-amino-4-phenyl-thiazole.

7. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline 5 with fi-diethylamino-ethylamine and simultaneously with 2-amino-4-(para-bromo-phenyl)-thiazole.

8. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline with j3-diethylamino-ethylamine and simultaneously with 10 2-amino-6-methyl-benzthiazole.

9. A process for the preparation of a quinazoline compound, which comprises heating a 2,4-dichloro-quinazoline with fl-diethylamino-ethylamine and simultaneously with 2-amino-4,6-dimethyl-benzthiaz01e.

I References Cited in the file of this patent Curd et al., J. Chem. Soc. 1947, 775-783. 

1. A PROCESS FOR THE PREPARATION OF A QUINAZOLINE COMPOUND, WHICH COMPRISES HEATING A 2,4-DICHLORO-QUINAZOLINE WITH A PRIMARY ALIPHATIC AMINE OF THE FORMULA 